# NM_000033.4(ABCD1):c.912C>G (p.Ala304=)

https://sugi.bio/variant/abcd1-p-ala304

## Summary

**ABCD1 p.Ala304= (c.912C>G)** is classified **Likely benign** in ABCD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-02). Absent from gnomAD v4.1; Associated with adrenoleukodystrophy.

**At a glance:** Likely benign · review: Single submitter · rsID rs1402264312 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCD1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to adrenoleukodystrophy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Prevalence | 1-9 / 1 000 000 (Israel) |
| Clinical trials | 48 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCD1 is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of X-linked adrenoleukodystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of vision — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Visual loss — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Dementia — Very frequent (99-80%)
- Hyperactivity — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005758/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCD1](https://sugi.bio/atlas/gene/ABCD1/) |
| Protein change (HGVS p.) | p.Ala304= |
| Coding change (HGVS c.) | c.912C>G |
| MANE Select transcript | [NM_000033](https://www.ncbi.nlm.nih.gov/nuccore/NM_000033) |
| dbSNP | [rs1402264312](https://www.ncbi.nlm.nih.gov/snp/rs1402264312/) |
| Variant type | single nucleotide variant |
| Location | chrX:153729243-153729243 (GRCh38) |
| ClinVar | [VCV2753377](https://www.ncbi.nlm.nih.gov/clinvar/variation/2753377/) |

**All HGVS expressions:** `LRG_1017:g.9376C>G`, `LRG_1017t1:c.912C>G`, `NC_000023.10:g.152994698C>G`, `NC_000023.11:g.153729243C>G`, `NG_009022.2:g.9376C>G`, `NG_023231.1:g.504G>C`, `NM_000033.4:c.912C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -1.42, GERP -3.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.34**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ABCD1** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **adrenoleukodystrophy** — Definitive (XL)

## Protein context {#protein}

Residue **304** lies in an α-helix; the abc transmembrane type-1 domain.

AlphaFold model confidence (whole protein): pLDDT 81.58, 43% of residues very-high.

**14 experimental structure(s)** (PDB): [7RR9](https://www.rcsb.org/structure/7RR9), [7RRA](https://www.rcsb.org/structure/7RRA), [7SHM](https://www.rcsb.org/structure/7SHM), [7SHN](https://www.rcsb.org/structure/7SHN), [7VR1](https://www.rcsb.org/structure/7VR1), [7VWC](https://www.rcsb.org/structure/7VWC).

## What this gene does {#gene-function}

*Describes the biological roles of ABCD1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ABCD1's established molecular role includes long-chain fatty acid transmembrane transporter activity. p.Ala304= falls in the abc transmembrane type-1 domain. In Reactome, ABCD1 is annotated in disease pathway(s) including **Defective ABCD1 causes ALD**.

**Disease mechanism (Reactome):** ABCD1 loss or alteration is curated in [Defective ABCD1 causes ALD](https://reactome.org/content/detail/R-HSA-5684045).

### Pathways affected {#pathways}

ABCD1 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCD1 causes ALD](https://reactome.org/content/detail/R-HSA-5684045) | curated |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |
| [Beta-oxidation of very long chain fatty acids](https://reactome.org/content/detail/R-HSA-390247) | curated |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | curated |
| [Linoleic acid (LA) metabolism](https://reactome.org/content/detail/R-HSA-2046105) | curated |
| [alpha-linolenic acid (ALA) metabolism](https://reactome.org/content/detail/R-HSA-2046106) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** long-chain fatty acid transmembrane transporter activity, ATP binding, ABC-type fatty-acyl-CoA transporter activity, ATP hydrolysis activity, enzyme binding, ATPase-coupled transmembrane transporter activity.

**Biological process:** very long-chain fatty acid metabolic process, fatty acid beta-oxidation, peroxisome organization, long-chain fatty acid import into peroxisome, positive regulation of fatty acid beta-oxidation, very long-chain fatty-acyl-CoA catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-02.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-02 |

## Associated conditions {#conditions}

[adrenoleukodystrophy](https://sugi.bio/atlas/disease/adrenoleukodystrophy/).

**Reported phenotype names (ClinVar):** Adrenoleukodystrophy, ADDISON DISEASE AND CEREBRAL SCLEROSIS, BRONZE SCHILDER DISEASE, X-Linked Adrenoleukodystrophy, MELANODERMIC LEUKODYSTROPHY, SIEMERLING-CREUTZFELDT DISEASE.

## Similar variants {#similar}

Related ABCD1 variant pages (same residue, condition, or type): [ABCD1 p.Ala304Pro](/variant/abcd1-p-ala304pro), [ABCD1 p.Ala304Thr](/variant/abcd1-p-ala304thr), [ABCD1 c.1635-2A>G](/variant/abcd1-c-1635-minus-2a-g), [ABCD1 c.1781-1G>C](/variant/abcd1-c-1781-minus-1g-c), [ABCD1 c.1781-1G>T](/variant/abcd1-c-1781-minus-1g-t), [ABCD1 c.1866-10G>A](/variant/abcd1-c-1866-minus-10g-a), [ABCD1 c.1866-1G>C](/variant/abcd1-c-1866-minus-1g-c), [ABCD1 c.1866-2A>T](/variant/abcd1-c-1866-minus-2a-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2753377). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*